Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review
- Authors: Valiev T.T.1,2, Semenova V.V.1,3, Ikonnikova A.Y.3, Petrova A.A.3, Belysheva T.S.1, Nasedkina T.V.3
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Affiliations:
- Blokhin National Medical Research Center of Oncology
- Sechenov First Moscow State Medical University (Sechenov University)
- Engelhardt Institute of Molecular Biology
- Issue: Vol 23, No 4 (2021)
- Pages: 622-627
- Section: CLINICAL ONCOLOGY
- URL: https://journals.rcsi.science/1815-1434/article/view/79133
- DOI: https://doi.org/10.26442/18151434.2021.4.201127
- ID: 79133
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Abstract
Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.
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##article.viewOnOriginalSite##About the authors
Timur T. Valiev
Blokhin National Medical Research Center of Oncology; Sechenov First Moscow State Medical University (Sechenov University)
Author for correspondence.
Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-1469-2365
D. Sci. (Med.), Prof.
Russian Federation, MoscowVera V. Semenova
Blokhin National Medical Research Center of Oncology; Engelhardt Institute of Molecular Biology
Email: sulpiridum@yandex.ru
ORCID iD: 0000-0002-9705-1001
Graduate Student
Russian Federation, MoscowAnna Yu. Ikonnikova
Engelhardt Institute of Molecular Biology
Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-8434-5916
junior researcher
Russian Federation, MoscowAlisa A. Petrova
Engelhardt Institute of Molecular Biology
Email: alisa7397396@gmail.com
ORCID iD: 0000-0002-7536-5683
Student
Russian Federation, MoscowTatiana S. Belysheva
Blokhin National Medical Research Center of Oncology
Email: klinderma@bk.ru
ORCID iD: 0000-0001-5911-553X
D. Sci. (Med.)
Russian Federation, MoscowTatiana V. Nasedkina
Engelhardt Institute of Molecular Biology
Email: tanased06@rambler.ru
ORCID iD: 0000-0002-2642-4202
D. Sci. (Biol.)
Russian Federation, MoscowReferences
- Махонова Л.А. Современные методы лечения острого лимфобластного лейкоза у детей. Автореф. дис. … канд. мед. наук. М., 1963; с. 14 [Mahonova LA. Sovremenie metody lechenya ostrogo limphoblastnogo leykoza u detey. Аvtoref. dis. … kand. med. nauk. Moscow, 1963; p. 14 (in Russian)].
- Demidowicz E, Pogorzała M, Łęcka M, et al. Outcome of pediatric acute lymphoblastic leukemia: sixty years of progress. Anticancer Res. 2019;39(9):5203-7. doi: 10.21873/anticanres.13717
- Валиев Т.Т. Лимфома Беркитта у детей: 30 лет терапии. Педиатрия. Журн. им. Г.Н. Сперанского. 2020;99(4):35-41 [Valiev TT. Lymphoma Berkitta u detey: 30 let terapii. Pediatriya. Zhurnal im. GN Speranskogo. 2020;99(4):35-41 (in Russian)].
- Kara MK, Peter DC, Qinglin P, et al. Response-adapted Therapy for the Treatment of Children with Newly Diagnosed High risk Hodgkin lymphoma (AHOD0831): a report from the Children's Oncology Group. Br J Haematol. 2019;187(1):39-48. doi: 10.1111/bjh.16014
- Sakura T, Hayakawa F, Sugiura I, et al. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018;32(3):626-32. doi: 10.1038/leu.2017.283
- ALL IC-BFM 2009. A randomized trial of the I-BFM-SG for the management of childhood non-B acute lymphoblastic leukemia final version of therapy protocol from August-14-2009. Available at: http://www.bialaczka.org/wp-content/uploads/2016/10/ALLIC_BFM_2009.pdf. Accessed: 28.02.2020 (in Russian)].
- ALL–MB 2015. Режим доступа: https://fnkc.ru/docs/ALLMB2015.pdf. Ссылка активна на 22.09.2021 [ALL–MB 2015. Available at: https://fnkc.ru/docs/ALLMB2015.pdf. Accessed: 22.09.2021 (in Russian)].
- Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia. J Clin Oncol. 2014;32(9):949-59. doi: 10.1200/JCO.2013.53.0808
- Schmiegelow K, Klaus Müller K, Mogensen SS, et al. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017;6:444. doi: 10.12688/f1000research.10768.1
- Sajith M, Pawar A, Bafna V, et al. Serum methotrexate level and side effects of high dose methotrexate infusion in pediatric patients with acute lymphoblastic leukaemia (ALL). Indian J Hematol Blood Transfus. 2020;36(1):51-8. doi: 10.1007/s12288-019-01144-3
- Lima A, Sousa H, Monteiro J, et al. Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers. Pharmacogenomics. 2014;15(12):1611-35. doi: 10.2217/pgs.14.116
- Fowler B. The folate cycle and disease in humans. Kidney Int Suppl. 2001;78:S221-9. doi: 10.1046/j.1523-1755.2001.59780221.x
- Suthandiram S, Gan GG, Zain SM, et al. Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics. 2014;15(11):1479-94. doi: 10.2217/pgs.14.97
- Cao M, Guo M, Wu DQ, Meng L. Pharmacogenomics of Methotrexate: current status and future outlook. Curr Drug Metab. 2018;19(14):1182-7. doi: 10.2174/1389200219666171227201047
- Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics. 2011;21(10):679-86. doi: 10.1097/FPC.0b013e328343dd93
- Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. doi: 10.2133/dmpk.dmpk-13-rv-119
- Esmaili MA, Kazemi A, Faranoush M, et al. Polymorphisms within methotrexate pathway genes: relationship between plasma methotrexate levels, toxicity experienced and outcome in pediatric acute lymphoblastic leukemia. Iran J Basic Med Sci. 2020;23(6):800-9. doi: 10.22038/ijbms.2020.41754.9858
- Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2013;13(6):498-506. doi: 10.1038/tpj.2012.44
- Fukushima H, Fukushima T, Sakai A, et al. Polymorphisms of MTHFR associated with higher relapse/death ratio and delayed weekly MTX administration in pediatric lymphoid malignancies. Leuk Res Treatment. 2013;2013:238528. doi: 10.1155/2013/238528
- Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxicology. 2021;458:152840. doi: 10.1016/j.tox.2021.152840
- Bernsen EC, Hagleitner MM, Kouwenberg TW, Hanff LM. Pharmacogenomics as a tool to limit acute and long-term adverse effects of chemotherapeutics: an update in pediatric oncology. Front Pharmacol. 2020;11:1184. doi: 10.3389/fphar.2020.01184
- Stamp LK, Roberts RL. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. Pharmacogenomics. 2011;12(10):1449-63. doi: 10.2217/pgs.11.86
- Trevino LR, Shimasaki N, Yang W, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009;27(35):5972-8. doi: 10.1200/JCO.2008.20.4156
- Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B. Blood. 2013;121(6):898-904. doi: 10.1182/blood-2012-08-452839
- Ramsey LB, Bruun GH, Yang W, et al. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res. 2012;22(1):1-8. doi: 10.1101/gr.129668.111
- Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG. Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis. Pharmacogenet Genomics. 2012;22(2):117-33. doi: 10.1097/FPC.0b013e32834ded2a
- Campbell JM, Bateman E, Stephenson MD, et al. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol. 2016;78(1):27-39. doi: 10.1007/s00280-016-3043-5
- Umerez M, Gutierrez-Camino Á, Muñoz-Maldonado C, et al. MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy. Pharmgenomics Pers Med. 2017;10:69-78. doi: 10.2147/PGPM.S107047
- Yao P, He X, Zhang R, et al. The influence of MTHFR genetic polymorphisms on adverse reactions after methotrexate in patients with hematological malignancies: a meta-analysis. Hematology. 2019;24(1):10-9. doi: 10.1080/10245332.2018.1500750
- Lee YH, Bae SC. Association of the ATIC 347 C/G polymorphism with responsiveness to and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2016;36(11):1591-9. doi: 10.1007/s00296-016-3523-2
- Cheng Y, Chen MH, Zhuang Q, et al. Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2021;68(5):e28858. doi: 10.1002/pbc.28858
- Gervasini G, de Murillo SG, Jiménez M, et al. Dihydrofolate reductase genetic polymorphisms affect methotrexate dose requirements in pediatric patients with acute lymphoblastic leukemia on maintenance therapy. J Pediatr Hematol Oncol. 2017;39(8):589-95. doi: 10.1097/MPH.0000000000000908
- Wang SM, Sun LL, Zeng WX, et al. Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2014;74(2):283-9. doi: 10.1007/s00280-014-2507-8
- Hegyi M, Arany A, Semsei AF, et al. Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma. Oncotarget. 2017;8(6):9388-98. doi: 10.18632/oncotarget.11543
- Uhlen M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi: 10.1126/science.1260419
- Huang Z, Tong HF, Li Y, et al. Effect of the polymorphism of folylpolyglutamate synthetase on treatment of high-dose methotrexate in pediatric patients with acute lymphocytic leukemia. Med Sci Monit. 2016;22:4967-73. doi: 10.12659/msm.899021
- Taylor ZL, Vang J, Lopez-Lopez E, et al. Systematic review of pharmacogenetic factors that influence high-dose methotrexate pharmacokinetics in pediatric Malignancies. Cancers (Basel). 2021;13(11):2837. doi: 10.3390/cancers13112837
- den Hoed MA, Lopez-Lopez E, te Winkel ML, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2015;15(3):248-54. doi: 10.1038/tpj.2014.63
- Maagdenberg H, Oosterom N, Zanen J, et al. Genetic variants associated with methotrexate-induced mucositis in cancer treatment: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;161:103312. doi: 10.1016/j.critrevonc.2021.103312
- Sorich MJ, Pottier N, Pei D, et al. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile. PLoS Med. 2008;5(4):e83. doi: 10.1371/journal.pmed.0050083
- Pietrzyk JJ, Bik-Multanowski M, Skoczen S, et al. Polymorphism of the thymidylate synthase gene and risk of relapse in childhood ALL. Leuk Res. 2011;35(11):1464-6. doi: 10.1016/j.leukres.2011.04.007
- de Beaumais TA, Jacqz-Aigrain E. Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children. Curr Drug Metab. 2012;13(6):822-34. doi: 10.2174/138920012800840400
- Roszkiewicz J, Michałek D, Ryk A, et al. SLCO1B1 variants as predictors of methotrexate-related toxicity in children with juvenile idiopathic arthritis. Scand J Rheumatol. 2021;50(3):213-7. doi: 10.1080/03009742.2020.1818821
- Mlakar V, Huezo-Diaz Curtis P, Satyanarayana Uppugunduri CR, et al. Pharmacogenomics in pediatric oncology: review of gene-drug associations for clinical use. Int J Mol Sci. 2016;17(9):1502. doi: 10.3390/ijms17091502
- Yousef AM, Farhad R, Alshamaseen D, et al. Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2019;83(4):755-762. doi: 10.1007/s00280-019-03776-8
- Nacional Cancer Institute. Cancer Therapy Evaluation Program: Common Toxicity Criteria Manual; National Cancer Institute: Bethesda, MD, USA, 1999; p. 1-29.
- Assaraf Y. The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resist Updat. 2006;9(4-5):227-46. doi: 10.1016/j.drup.2006.09.001
- Relton CL, Wilding CS, Pearce MS, et al. Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet. 2004;41(4):256-60. doi: 10.1136/jmg.2003.010694
- Zinck JW, MacFarlane AJ. Approaches for the identification of genetic modifiers of nutrient dependent phenotypes: examples from folate. Front Nutr. 2014;1:8. doi: 10.3389/fnut.2014.00008
- Amos W, Driscoll E, Hoffman JI. Candidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease? Proc Biol Sci. 2011;278(1709):1183-8. doi: 10.1098/rspb.2010.1920.
- Pavlovic S, Kotur N, Stankovic B, et al. Pharmacogenomic and pharmacotranscriptomic profiling of childhood acute lymphoblastic leukemia: paving the way to personalized treatment. Genes (Basel). 2019;10(3):191. doi: 10.3390/genes10030191